
Am J Psychiatry 2008; 165:1163-1171
(published online June 2, 2008; doi: 10.1176/appi.ajp.2008.07111711)
© 2008 American Psychiatric Association
Variants in Nicotinic Receptors and Risk for Nicotine Dependence
Laura Jean Bierut, M.D.,
Jerry A. Stitzel, Ph.D.,
Jen C. Wang, Ph.D.,
Anthony L. Hinrichs, Ph.D.,
Richard A. Grucza, Ph.D.,
Xiaoling Xuei, Ph.D.,
Nancy L. Saccone, Ph.D.,
Scott F. Saccone, Ph.D.,
Sarah Bertelsen, M.A.,
Louis Fox, B.S.,
William J. Horton, B.S.,
Naomi Breslau, Ph.D.,
John Budde, B.S.,
C. Robert Cloninger, M.D.,
Danielle M. Dick, Ph.D.,
Tatiana Foroud, Ph.D.,
Dorothy Hatsukami, Ph.D.,
Victor Hesselbrock, Ph.D.,
Eric O. Johnson, Ph.D.,
John Kramer, Ph.D.,
Samuel Kuperman, M.D.,
Pamela A.F. Madden, Ph.D.,
Kevin Mayo, B.S.,
John Nurnberger Jr., M.D., Ph.D.,
Ovide Pomerleau, Ph.D.,
Bernice Porjesz, Ph.D.,
Oliver Reyes, B.S.,
Marc Schuckit, M.D.,
Gary Swan, Ph.D.,
Jay A. Tischfield, Ph.D.,
Howard J. Edenberg, Ph.D.,
John P. Rice, Ph.D., and
Alison M. Goate, D.Phil.
OBJECTIVE: A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the 5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking. METHOD: Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function. RESULTS: A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown. CONCLUSIONS: This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.
Related Articles:
-
Nicotine Addiction
- Wade Berrettini
Am J Psychiatry 2008 165: 1089-1092.
[Full Text]
[PDF]
-
In This Issue
Am J Psychiatry 2008 165: A36.
[Full Text]
[PDF]
This article has been cited by other articles:

|
 |

|
 |
 
T. B. Baker, R. B. Weiss, D. Bolt, A. von Niederhausern, M. C. Fiore, D. M. Dunn, M. E. Piper, N. Matsunami, S. S. Smith, H. Coon, et al.
Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes
Nicotine Tob Res,
July 1, 2009;
11(7):
785 - 796.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. Wu, Z. Hu, D. Yu, L. Huang, G. Jin, J. Liang, H. Guo, W. Tan, M. Zhang, J. Qian, et al.
Genetic Variants on Chromosome 15q25 Associated with Lung Cancer Risk in Chinese Populations
Cancer Res.,
June 15, 2009;
69(12):
5065 - 5072.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. Shiraishi, T. Kohno, H. Kunitoh, S.-i. Watanabe, K. Goto, Y. Nishiwaki, Y. Shimada, H. Hirose, I. Saito, A. Kuchiba, et al.
Contribution of nicotine acetylcholine receptor polymorphisms to lung cancer risk in a smoking-independent manner in the Japanese
Carcinogenesis,
January 1, 2009;
30(1):
65 - 70.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
V. L. Stevens, L. J. Bierut, J. T. Talbot, J. C. Wang, J. Sun, A. L. Hinrichs, M. J. Thun, A. Goate, and E. E. Calle
Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking
Cancer Epidemiol. Biomarkers Prev.,
December 1, 2008;
17(12):
3517 - 3525.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. R. Spitz, C. I. Amos, Q. Dong, J. Lin, and X. Wu
The CHRNA5-A3 Region on Chromosome 15q24-25.1 Is a Risk Factor Both for Nicotine Dependence and for Lung Cancer
J Natl Cancer Inst,
November 5, 2008;
100(21):
1552 - 1556.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
W. Berrettini
Nicotine Addiction
Am J Psychiatry,
September 1, 2008;
165(9):
1089 - 1092.
[Full Text]
[PDF]
|
 |
|
Get information about faster international access.
a>
Privacy Policy
Copyright © 2008
American Psychiatric Association.
All rights reserved.
Home
| Search
| Current Issue
| Past Issues
| Subscribe
| All APPI Journals
| Help
| Contact Us
|